Biomedical subjects

Gianni Pezzoli

Publications and source records attributed to Gianni Pezzoli.

At least 19 recordsLinked to original sources

PubMed2025

Genome-wide association study of copy number variations in Parkinson's disease.

OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

Journal Article↗

PubMed2007

Valvular heart disease and the use of dopamine agonists for Parkinson's disease.

BACKGROUND: Ergot-derived dopamine receptor agonists, often used in the treatment of Parkinson's disease, have been associated with an increased risk of valvular heart disease. METHODS: We performed an echocardiographic prevalence study in 155 patients taking dopamine agonists for Parkinson's disease (pergolide, 64 patients; cabergoline, 49; and non-ergot-derived dopamine agonists, 42) and 90 control subjects. Valve regurgitation was assessed according to American Society of Echocardiography recommendations. The mitral-valve tenting area was also measured and used as a quantitative index for leaflet stiffening and apical displacement of leaflet coaptation. RESULTS: Clinically important regurgitation (moderate to severe, grade 3 to 4) in any valve was found with significantly greater frequency in patients taking pergolide (23.4%) or cabergoline (28.6%) but not in patients taking non-ergot-derived dopamine agonists (0%), as compared with control subjects (5.6%). The relative risk for moderate or severe valve regurgitation in the pergolide group was 6.3 for mitral regurgitation (P=0.008), 4.2 for aortic regurgitation (P=0.01), and 5.6 for tricuspid regurgitation (P=0.16); corresponding relative risks in the cabergoline group were 4.6 (P=0.09), 7.3 (P<0.001), and 5.5 (P=0.12). The mean mitral tenting area was significantly greater in ergot-treated patients and showed a linear relationship with the severity of mitral regurgitation. Patients treated with ergot derivatives who had grade 3 to 4 regurgitation of any valve had received a significantly higher mean cumulative dose of pergolide or cabergoline than had patients with lower grades. CONCLUSIONS: The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists, as compared with control subjects. These findings should be considered in evaluating the risk-benefit ratio of treatment with ergot derivatives.

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PubMed2007

Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum.

Autosomal recessive parkinsonism is a genetic condition closely resembling Parkinson disease, the only distinguishing features being an earlier age at onset and a slower disease progression. Three causative genes have been identified so far. While exon rearrangements are frequently encountered in the Parkin gene, most PINK1 mutations are represented by single nucleotide changes. We report a sporadic parkinsonian patient carrying a deletion of the entire PINK1 gene and a splice site mutation (g.15445_15467del23) which produces several aberrant mRNAs. This report expands the genotypic spectrum of PINK1 mutations, with relevant implications for molecular analysis of this gene.

Amino Acid Sequence↗

PubMed2007

Extradural motor cortex stimulation in Parkinson's disease.

Extradural motor cortex stimulation (EMCS) is a surgical procedure proposed for patients with advanced Parkinson's disease (PD) who cannot undergo deep brain stimulation (DBS). Five PD patients with motor fluctuations and dyskinesia underwent EMCS of the left hemisphere. All fulfilled CAPSIT criteria for DBS, with the exception of age > 70 years. Patients were assessed preoperatively and 6 months after surgery on and off medications, with stimulator on, and 2 weeks later with stimulator off. Outcome measures included changes in mean medication dosage (levodopa and dopamine agonists), Unified Parkinson's Disease Rating Scale (UPDRS Parts II-III and Item 39), and dyskinesias (Abnormal Involuntary Movements Scale [AIMS]). We found no significant mean changes following EMCS. However, there was a trend for a reduction of mean daily medication intake (-30%) and AIMS (-19%). There were 3 patients who reported reduced OFF time (UPDRS Item 39) and 4 of 5 who felt a subjective benefit in stability and gait. In our PD cohort, EMCS induced no objective benefit, although some subjective improvement was reported mostly on axial symptoms.

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PubMed2006

LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample.

We analysed the Leucine-Rich Repeat Kinase 2 (LRRK2) gene for the G2019S mutation in 1245 consecutive, unrelated patients with primary degenerative parkinsonism, and collected information on medical history, motor, cognitive and neuropsychiatric functions to characterize the clinical phenotype associated to the G2019S mutation. The mutation was detected in heterozygous state in 19 probands (1.7%), and in five additional affected relatives. Clinical features in carriers were those of typical, idiopathic Parkinson's disease. However, behavioural abnormalities were frequent (87%), suggesting a more widespread limbic involvement in G2019S carriers.

Adult↗

PubMed2006

Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.

BACKGROUND: The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). OBJECTIVE: To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. DESIGN: Clinical and genetic study. SETTING: Twenty collaborative clinical sites. PATIENTS: Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. MAIN OUTCOME MEASURES: Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. RESULTS: Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04). CONCLUSIONS: These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

Adult↗

PubMed2006

Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration.

We report on a patient with late-onset, pantothenate kinase-associated neurodegeneration (PKAN) who revealed two new heterozygous mutations at gene testing and showed asymmetric moderately reduced striatal dopamine transporter binding with single photon emission computed tomography, possibly due to prolonged neuroleptic treatment. These findings expand the genetic and imaging spectrum of this rare disorder.

Age Factors↗

PubMed2006

Protein intake in Parkinsonian patients using the EPIC food frequency questionnaire.

The dietary habits of 45 Italian patients with Parkinson's disease (PD) and their spouses were investigated using the EPIC food frequency questionnaire. Average daily energy intake was similar, but PD patients consumed significantly more vegetable proteins and carbohydrates (both +18%; P = 0.01 and P = 0.001, respectively). Daily protein intake, which interferes with levodopa absorption, was 50% higher than the recommended daily allowance (1.2 vs. 0.8 g/kg) in both PD patients and spouses and was significantly higher in patients with moderate/severe symptoms (1.27 +/- 0.29 vs. 1.07 +/- 0.28 g/kg; P < 0.001). In patients taking levodopa, there was a correlation between daily levodopa dosage and protein intake (P = 0.027). Dietary habits of patients with advanced and/or fluctuating PD should always be checked, with particular reference to protein intake.

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PubMed2006

Randomized study of sertraline and low-dose amitriptyline in patients with Parkinson's disease and depression: effect on quality of life.

We assessed the effect of 3-month treatment of sertraline (50 mg) or low-dose amitriptyline (25 mg) on depression and quality of life in 31 patients with Parkinson's disease in a prospective single-blind randomized study. Both drugs significantly reduced the Hamilton Depression Rating Scale (HDRS-17) score. Completion rate was 75% for sertraline (12 of 16) and 73% for amitriptyline (11 of 15). Responder rate (HDRS-17 score reduction >/= 50%) was 83.3% for sertraline and 72.7% for amitriptyline. Sertraline but not amitriptyline treatment determined a significant benefit on quality of life (PDQ-39 scale). We found no change in Unified Parkinson's Disease Rating Scale scores. However, the improvement in specific PDQ-39 subscores (mobility, activities of daily living, and stigma) suggests that depression affects patient self-perception of motor function and further emphasizes the need for its treatment.

Amitriptyline↗

PubMed2006

Striatal dopamine transporter binding in Parkinson's disease associated with the LRRK2 Gly2019Ser mutation.

We measured striatal dopamine transporter binding using [(123)I]ioflupane and SPECT in patients with Parkinson's disease associated with the LRRK2 (PARK8) Gly2019Ser gene mutation (LRRK2-PD) and in gene-negative patients with idiopathic Parkinson's disease (IPD) of comparable disease duration and severity. The LRRK2-PD group consisted of a total of 10 patients (3 sporadic) with mean age 62 +/- 14 years, disease duration 9 +/- 3 years, and UPDRS III motor score 21.60 +/- 6.65. The control IPD group consisted of 15 patients with mean age 59 +/- 9 years, disease duration 9 +/- 5 years, and UPDRS III motor score 23.80 +/- 8.69. [(123)I]ioflupane-specific uptake ratios were calculated for caudate nucleus and putamen using the occipital cortex as reference region. We found no differences between the LRRK2-PD group and IPD in all items studied. In particular, putamen and caudate uptake values as well as side asymmetry indexes and putamen/caudate ratios all revealed comparable between-group values. We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD.

Amino Acid Substitution↗

PubMed2006

Special low-protein foods ameliorate postprandial off in patients with advanced Parkinson's disease.

Protein intake interferes with levodopa therapy. Patients with advanced Parkinson's disease (PD) should restrict daily protein intake and shift protein intake to the evening. For further reduction of protein intake in the first part of the day, special low-protein products (LPP) should be used instead of normal food products at breakfast and lunch. We studied the efficacy of LPP on postprandial off periods, in PD patients on levodopa therapy. The methods included a randomized, cross-over, single-blind, pilot clinical trial comparing a 2-month balanced diet with a 2-month LPP diet in 18 PD patients with motor fluctuations. The off phases were significantly shorter after LPP diet than after balanced diet (postprandial off, 49 +/- 73 min vs. 79 +/- 72 min and total off, 164 +/- 148 min vs. 271 +/- 174 min, both P < 0.0001). Moreover, a reduction in total off time during LPP diet (3.3 +/- 2.7 hr vs. 4.7 +/- 3.3 hr, P < 0.0001), occurred also in the 9 patients who did not experience subjective benefit. No significant changes in hematological and biochemical variables or body composition were recorded; a slight reduction in body weight (mean, -1.8%) was observed. Consumption of LPP in the first part of the day ameliorates off periods in PD patients, but additional studies including pharmacokinetics are needed.

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PubMed2006

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

Adult↗

PubMed2005

Long-term efficacy and safety of pramipexole in advanced Parkinson's disease: results from a European multicenter trial.

A double-blind, placebo-controlled study with a subsequent open-label phase was conducted in 354 patients with Parkinson's disease (PD) and motor fluctuations under individually adjusted therapy with levodopa. During the double-blind phase 174 patients received pramipexole and 180 placebo. In agreement with previous studies, pramipexole treatment improved UPDRS sum scores of parts II and III by 30% and off times by approximately 2.5 hours per day. Differences between the treatment groups became significant at a daily dose of 0.75 mg of pramipexole dihydrochloride. We, furthermore, performed post hoc analyses with respect to resting tremor and depression. Patients with pronounced resting tremor derived a clear benefit from pramipexole treatment compared with placebo. In addition, pramipexole significantly improved the subitems motivation/initiative and depression in a subpopulation with increased Unified Parkinson's Disease Rating Scale I scores at the time of inclusion. There were 262 patients who were subsequently enrolled into the open-label study featuring a maximum duration of up to 57 months. Statistical analysis revealed good long-term efficacy and tolerability of pramipexole. Overall, only a low prevalence of somnolence was found. In summary, this study provides additional level I evidence of the usefulness of pramipexole, suggests a particular tremorlytic and a possible antidepressant action of this compound, and addresses for the first time its efficacy and safety during long-term administration in advanced PD.

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PubMed2005

Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians.

It has been proposed that European mitochondrial DNA (mtDNA) haplogroups J and K, and their shared 10398G single-nucleotide polymorphism (SNP) in the ND3 gene, are protective from Parkinson's disease (PD). We evaluated the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset (>50, <65 years of age) idiopathic PD vs two groups of ethnic-matched controls. Neither the frequencies of haplogroup J nor that of 10398G were significantly different. However, the frequency of haplogroup K was significantly lower in PD. Stratification by sex and age indicated that the difference in the distribution of haplogroup K was more prominent in >50 year old males. In spite of the common 10398G SNP, haplogroups J and K belong to widely diverging mitochondrial clades, a consideration that may explain the different results obtained for the two haplogroups in our cohorts. Our study suggests that haplogroup K might confer a lower risk for PD in Italians, corroborating the idea that the mitochondrial oxidative phosphorylation pathway is involved in the susceptibility to idiopathic PD.

Age of Onset↗

PubMed2004

The neuromelanin of human substantia nigra: physiological and pathogenic aspects.

Neuromelanin (NM) accumulates as a function of age in normal human substantia nigra (SN) but is relatively depleted in the SN of patients with Parkinson disease (PD). Several studies have been performed to further our understanding of the role of NM in neuronal aging and neurodegenerative mechanisms of PD. To this purpose, NM from human SN was isolated and its structure and molecular interactions were investigated. Cysteinyl-dopamine was shown to be one precursor of NM synthesis. A striking affinity of NM for specific metals, lipids, drugs and pesticides was found in vitro, and in animal and human brain postmortem studies. Because of these affinities, NM seems to play a protective role in the human brain by blocking toxic molecules. On the other hand, experiments in cell culture indicate that NM can activate microglia, eliciting the release of cytotoxic factors that can induce neurodegeneration.

Aging↗

PubMed2003

Body weight gain rate in patients with Parkinson's disease and deep brain stimulation.

We evaluated body weight changes in patients with Parkinson's disease (PD) after electrode implantation for deep brain stimulation (DBS) in the subthalamic nucleus (STN) in relation to clinical improvement. Thirty PD patients who received STN DBS were included (22 men, 8 women; mean age, 60.0 +/- 7.1 years; mean PD duration, 13.5 +/- 3.7 years; mean body mass index [BMI], 21.6 +/- 3.0 kg/m2). Body weight, physical activity, and Unified Parkinson's Disease Rating Scale (UPDRS) scores were noted before and 3 and 12 months after the procedure. Significant weight gain occurred in 29 patients; the mean increase was 14.8 +/- 9.8% of initial body weight in 1 year. Of the patients, 46.5% reported weight gain in the first 3 months, 21.4% gradual weight gain in the first 6 months, and 32.1% a slow increase for 1 year. Mean BMI increased up to 24.7 +/- 3.7 kg/m2. After 1 year, mean UPDRS motor score improved significantly in off and in on; and therapy complications improved by 91.0 +/- 17.0%. BMI changes at 3 and 12 months were significantly correlated to dyskinesia score changes, and levodopa dosage was not. In PD, STN DBS produces not only symptom control, but also weight gain. DBS candidates should be given nutritional counseling before the intervention to prevent rapid and/or excessive weight gain.

Body Mass Index↗

PubMed2002

Tc-99m ethylene cysteinate dimer SPECT in the differential diagnosis of parkinsonism.

Positron emission tomography (PET) and network analysis have been used to identify a reproducible pattern of regional metabolic covariation that is associated with idiopathic Parkinson's disease (PD). The activity of this PD-related pattern can be quantified in individual subjects and used to discriminate PD patients from atypical parkinsonians. Because PET is not commonly available, we sought to determine whether similar discrimination could be achieved using more routine single photon emission computed tomography (SPECT) perfusion methods. Twenty-three subjects with PD (age, 63 +/- 9 years), 22 subjects with multiple system atrophy (MSA; age, 64 +/- 7 years), and 20 age-matched healthy controls (age, 62 +/- 13 years) underwent SPECT imaging of regional cerebral perfusion with Tc-99m ethylene cysteinate dimer (ECD). Using network analysis, we determined whether a PD-related pattern existed in the SPECT data, and whether its expression discriminated PD from MSA patients. Additionally, we compared the accuracy of group discrimination achieved by this pattern with that of the PET-derived PD-related pattern applied to the SPECT data. Network analysis of the SPECT data identified a significant pattern characterized by relative increases in cerebellar, lentiform, and thalamic perfusion covarying with decrements in the frontal operculum and in the medial temporal cortex. Subject scores for this pattern discriminated PD patients from controls (P < 0.01) and from MSA patients (P < 0.03). Subject scores for the PET-derived PD-related pattern computed in the individual SPECT scans more accurately distinguished PD patients from controls (P < 0.005) and from MSA patients (P = 0.0002). A significant PD-related covariance pattern can be identified in SPECT perfusion data. Moreover, the disease related pattern identified previously with PET can be applied to individual SPECT perfusion scans to provide group discrimination between PD patients, healthy controls, and individuals with MSA. Because of significant individual subject overlap between groups, however, the clinical utility of this method in the differential diagnosis of Parkinsonism remains uncertain.

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PubMedDate not supplied

Thin section MR study of the basal ganglia in the differential diagnosis between striatonigral degeneration and Parkinson disease.

PURPOSE: Signal abnormalities within the putamen in MRI have been related to tissue degeneration in the striatonigral variant of multiple system atrophy (MSA-P). While previous work demonstrated the high specificity of these MR findings, sensitivity rates were unsatisfactory. We evaluated the specificity and sensitivity of an acquisition protocol using thin section MRI to differentiate MSA-P from Parkinson disease (PD). METHOD: Axial 3-mm-thick conventional T2 and proton density spin echo images at the level of basal ganglia were acquired at 1.5 T in 24 patients with MSA-P and 27 patients with PD. RESULTS: We found an abnormal putaminal T2 hypointensity in 21 of 24 MSA-P patients (87.5% sensitivity) and a proton density hyperintensity in 20 of 24 MSA-P patients (83.3% sensitivity). Three among 27 PD patients had an abnormal putaminal T2 hypointensity (88.8% specificity) and there were no proton density abnormalities (100% specificity). CONCLUSION: Our thin section conventional spin echo protocol showed a substantial increase in MR sensitivity compared with previous reports. We believe that a better depiction of even mild signs of degeneration in the putamen may allow a more widespread use of this technique in the differential diagnosis of parkinsonisms.

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